1. |
Mleczko M.♦, Postema M.♦, Schmitz G.♦, Discussion of the application of finite Volterra series for the modeling of the oscillation behavior of ultrasound contrast agents,
APPLIED ACOUSTICS, ISSN: 0003-682X, DOI: 10.1016/j.apacoust.2008.09.012, Vol.70, No.10, pp.1363-1369, 2009Abstract: Ultrasound contrast agents consist of microbubbles with diameters in the micrometer range. Excited by ultrasound, these bubbles exhibit highly nonlinear oscillation. While well developed physical models for microbubble oscillation exist, the efficiency of pulse sequences for sensitive microbubble detection is discussed based on simple mathematical models of general nonlinearity. Typically, Taylor series are used to model microbubble nonlinearity for the development of detection schemes. Recently, pulse sequences were proposed which exploit nonlinear memory of microbubbles, a property that cannot be modeled by a Taylor series but can be explained using a Volterra series. Therefore, this paper discusses and evaluates the usage of Volterra series for the modeling of the scattering behavior of contrast agent microbubbles. A numerically stable linear estimation algorithm is implemented to determine a third order Volterra model for a free gas bubble with a resting radius r0 1⁄4 1 lm. For insonification pressures up to 100 kPa, the identified model allowed for a mean-square error of less than 16 dB with respect to the reference signal. Analysis of the response to narrowband signals showed that the achievable mean-square error is further reduced for the bandwidth available to typical ultrasound transducers used for clinical diagnostics. Keywords: Ultrasound contrast agent, Microbubble, Volterra series, Rayleigh–Plesset, System identification, Nonlinear oscillation Affiliations:
Mleczko M. | - | other affiliation | Postema M. | - | other affiliation | Schmitz G. | - | other affiliation |
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2. |
Postema M.♦, Schmitz G.♦, Ultrasonic bubbles in medicine: Influence of the shell,
Ultrasonics Sonochemistry, ISSN: 1350-4177, DOI: 10.1016/j.ultsonch.2006.09.013, Vol.14, pp.438-444, 2007Abstract: Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification, and demonstrate highly nonlinear behavior, ameliorating their detectability. (Potential) medical applications involving the ultrasonic disruption of contrast agent microbubble shells include release-burst imaging, localized drug delivery, and noninvasive blood pressure measurement. To develop and enhance these techniques, predicting the cracking behavior of ultra- sound-insonified encapsulated microbubbles has been of importance. In this paper, we explore microbubble behavior in an ultrasound field, with special attention to the influence of the bubble shell. A bubble in a sound field can be considered a forced damped harmonic oscillator. For encapsulated microbubbles, the presence of a shell has to be taken into account. In models, an extra damping parameter and a shell stiffness parameter have been included, assuming that Hooke’s Law holds for the bubble shell. At high acoustic amplitudes, disruptive phenomena have been observed, such as microbubble fragmentation and ultrasonic cracking. We analyzed the occurrence of ultrasound contrast agent fragmentation, by simulating the oscillating behavior of encapsulated microbubbles with various sizes in a harmonic acoustic field. Fragmentation occurs exclusively during the collapse phase and occurs if the kinetic energy of the collapsing microbubble is greater than the instantaneous bubble surface energy, provided that surface instabilities have grown big enough to allow for break-up. From our simulations it follows that the Blake critical radius is not a good approximation for a fragmentation threshold.
We demonstrated how the phase angle differences between a damped radially oscillating bubble and an incident sound field depend on shell parameters. Keywords: Ultrasound contrast agent, Shell disruption, Fragmentation threshold, Oscillation phase angle, Shell elasticity, Shell friction Affiliations:
Postema M. | - | other affiliation | Schmitz G. | - | other affiliation |
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3. |
Mleczko M.♦, Wilkening W.G.♦, Postema M.♦, Schmitz G.♦, Optimisation of pulse sequences for ultrasound contrast agent imaging,
Biomedical Engineering-Biomedizinische Technik, ISSN: 1862-278X, Vol.52, No.S1, Supplement, pp.G2-1-2, 2007 | |
4. |
Postema M.♦, ten Cate F.J.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Generation of a droplet inside a microbubble with the aid of an ultrasound contrast agent: first result,
Letters in Drug Design and Discovery, ISSN: 1570-1808, DOI: 10.2174/157018007778992847, Vol.4, pp.74-77, 2007Abstract: New ultrasound contrast agents that incorporate a therapeutic compound have become of interest. Such an ultrasound contrast agent particle might act as the vehicle to carry a drug or gene load to a perfused region of interest. The load could be released with the assistance of ultrasound. Generally, an increase in shell thickness increases the acoustic amplitude needed to disrupt a bubble. High acoustic amplitudes, however, have been associated with unwanted effects on cells. It would be interesting to incorporate a droplet containing drugs or genes inside a microbubble carrier. A liquid core surrounded by a gas encapsulation has been referred to as antibubble. In this paper, the creation of an antibubble with the aid of ultrasound has been demonstrated with high-speed photography. Keywords: Antibubble, Ultrasound contrast agent, Drug delivery, High-speed photography Affiliations:
Postema M. | - | other affiliation | ten Cate F.J. | - | other affiliation | Schmitz G. | - | other affiliation | de Jong N. | - | other affiliation | van Wamel A. | - | other affiliation |
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5. |
Postema M.♦, Schmitz G.♦, Bubble dynamics involved in ultrasonic imaging,
Expert Review of Molecular Diagnostics, ISSN: 1473-7159, DOI: 10.1586/14737159.6.3.493, Vol.6, No.3, pp.493-502, 2006Abstract: In clinical ultrasound, blood cells cannot be differentiated from surrounding tissue, due to the low acoustic impedance difference between blood cells and their surroundings. Resonant gas bubbles introduced in the bloodstream are ideal markers, if rapid dissolution can be prevented. Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification. Microbubbles with thin lipid shells have demonstrated highly nonlinear behavior. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical microbubbles have been modeled. Several detection techniques have been proposed to improve the detectability of the microbubbles. A new generation of contrast agents, with special targeting ligands attached to the shells, may assist the imaging of nonphysical properties of target tissue. Owing to microbubble-based contrast agents, ultrasound is becoming an even more important technique in clinical diagnostics. Keywords: Detection, Harmonic imaging, Herring equation, Microbubble, Resonance, RPNNP equation, Scattering, Targeted imaging, Ultrasound, Ultrasound contrast agent Affiliations:
Postema M. | - | other affiliation | Schmitz G. | - | other affiliation |
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6. |
Postema M.♦, Bouakaz A.♦, ten Cate F.J.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Nitric oxide delivery by ultrasonic cracking: Some limitations,
Ultrasonics, ISSN: 0041-624X, DOI: 10.1016/j.ultras.2006.06.003, Vol.44, pp.e109-e113, 2006Abstract: Nitric oxide (NO) has been implicated in smooth muscle relaxation. Its use has been widespread in cardiology. Due to the effective scavenging of NO by hemoglobin, however, the drug has to be applied locally or in large quantities, to have the effect desired. We propose the use of encapsulated microbubbles that act as a vehicle to carry the gas to a region of interest. By applying a burst of high-amplitude ultrasound, the shell encapsulating the gas can be cracked. Consequently, the gas is released upon which its dissolution and diffusion begins. This process is generally referred to as (ultra)sonic cracking.
To test if the quantities of released gas are high enough to allow for NO-delivery in small vessels (ø < 200 lm), we analyzed high-speed optical recordings of insonified stiff-shelled microbubbles. These microbubbles were subjected to ultrasonic cracking using 0.5 or 1.7 MHz ultrasound with mechanical index MI > 0.6. The mean quantity released from a single microbubble is 1.7 fmol. This is already more than the NO production of a 1 mm long vessel with a 50 lm diameter during 100 ms. However, we simulated that the dissolution time of typical released NO microbubbles is equal to the half-life time of NO in whole blood due to scavenging by hemoglobin (1.8 ms), but much smaller than the extravascular half-life time of NO (>90 ms).
We conclude that ultrasonic cracking can only be a successful means for nitric oxide delivery, if the gas is released in or near the red blood cell-free plasma next to the endothelium. A complicating factor in the in vivo situation is the variation in blood pressure. Although our simulations and acoustic measurements demonstrate that the dissolution speed of free gas increases with the hydrostatic pressure, the in vitro acoustic amplitudes suggest that the number of released microbubbles decreases at higher hydrostatic pressures. This indicates that ultrasonic cracking mostly occurs during the expansion phase. Keywords: Nitric oxide, Sonic cracking Affiliations:
Postema M. | - | other affiliation | Bouakaz A. | - | Université François Rabelais (FR) | ten Cate F.J. | - | other affiliation | Schmitz G. | - | other affiliation | de Jong N. | - | other affiliation | van Wamel A. | - | other affiliation |
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7. |
Chaudhry S.K.♦, Khaled W.♦, Postema M.♦, Ermert H.♦, Schmitz G.♦, Accelerated block-based 2D motion estimation for pre-processing in elastography,
Biomedical Engineering-Biomedizinische Technik, ISSN: 1862-278X, Vol.50, No.S1, Supplement, pp.637-638, 2005Abstract: In intravascular ultrasound, we investigate vessel motion due to pulsating blood flow. Relatively large lateral displacements are observed. To incorporate these, we propose an initially 2D displacement estimation based on an accelerated block matching algorithm for preprocessing. In this paper, an accelerated algorithm based on the Successive Elimination Algorithm is described. Furthermore, we evaluated the algorithm based on intravascular ultrasound data. The proposed algorithm is compared search time and identical motion field. Affiliations:
Chaudhry S.K. | - | other affiliation | Khaled W. | - | other affiliation | Postema M. | - | other affiliation | Ermert H. | - | other affiliation | Schmitz G. | - | other affiliation |
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8. |
Mienkina M.P.♦, Postema M.♦, Hansen C.♦, Schmitz G.♦, Modelling ultrasonic backscattering of an SPIO-MRI contrast agent,
Biomedical Engineering-Biomedizinische Technik, ISSN: 1862-278X, Vol.50, No.S1, Supplement, pp.750-751, 2005Abstract: The ultrasonic backscatter coefficient (BSC) of superparamagnetic iron oxide (SPIO) nanoparticles, which are used as a liver MRI contrast agent, was simulated using a Yagi backscattering model. The BSC of SPIO cores that are aggregated in the lysosomes of Kupffer cells is significantly higher (85 dB) than the BSC of non- aggregated SPIO cores. Considering in vivo concentrations, the aggregated SPIO does not elevate the BSC of the liver markedly (9x10-6 dB). Thus, the reported visibility of SPIO in clinical ultrasound cannot be explained by classical scattering theory. Other non-linear effects need to be taken into account. Affiliations:
Mienkina M.P. | - | other affiliation | Postema M. | - | other affiliation | Hansen C. | - | CERN (CH) | Schmitz G. | - | other affiliation |
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9. |
Postema M.♦, de Jong N.♦, Schmitz G.♦, The physics of nanoshelled microbubbles,
Biomedical Engineering-Biomedizinische Technik, ISSN: 1862-278X, Vol.50, No.S1, Supplement, pp.748-749, 2005Abstract: Nanoshelled microbubbles are suitable markers for perfused areas in ultrasonic imaging, and have potential applications in therapy. With radii up to 5 microns, their resonance frequencies are in the lower megahertz range. We explored the physics of nanoshelled microbubbles, with special attention to the influence of the nanoshell on the oscillation offset with respect to the driving phase. Microbubbles above resonance size oscillate π rad out of phase with respect to microbubbles under resonance size. As the damping becomes less, this transition in offset becomes more abrupt. Therefore, the damping due to the friction of the nanoshell can be derived from this abruptness. We support our results with some high-speed optical observations of oscillating microbubbles in an ultrasonic field. Affiliations:
Postema M. | - | other affiliation | de Jong N. | - | other affiliation | Schmitz G. | - | other affiliation |
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10. |
Postema M.♦, ten Cate F.J.♦, Lancée C.T.♦, Schmitz G.♦, de Jong N.♦, van Wamel A.♦, Ultrasonic destruction of medical microbubbles: an overview,
Ultraschall in der Medizin, ISSN: 0172-4614, Vol.26, pp.S32-S33, 2005Abstract: Purpose:
Ultrasound contrast agents consist of bubbles in the micrometer range encapsulated by nanoshells. These medical microbubbles oscillate linearly upon insonification at low acoustic amplitudes, but demonstrate highly nonlinear, destructive behavior at relatively high acoustic amplitudes. Therefore, medical microbubbles have been investigated for their potential applications in local drug and gene delivery. We used fast-framing photography at more than a million frames per second to investigate medical microbubbles in a diagnostic ultrasonic field. In this presentation, we give an overview of the physical mechanisms of medical microbubble destruction.
Methods and Materials:
Three ultrasound contrast agents were studied with high-speed photography during insonification. The agents were inserted through a cellulose capillary with a diameter of 0.2mm. The capillary was positioned below a microscope whose optical focus coincided with the ultrasonic focus. We captured images of insonified medical bubbles at higher frame rates than the ultrasonic frequency transmitted (typically 0.5MHz). The acoustic amplitudes corresponded to mechanical indices between 0.03 and 0.8. To compare theory and experiments, we simulated insonified medical microbubble behavior, based on the behavior of large, unencapsulated bubbles in an acoustic field.
Results:
At low acoustic amplitudes (mechanical index <0.1) bubbles pulsate moderately, as predicted from theory. At high amplitudes (mechanical index >0.6) their elongated expansion phase is followed by a violent collapse. Microbubbles have been observed to coalesce (merge), fragment, crack, and jet (act as a microsyringe) during one single ultrasonic cycle. From our observations of jetting through medical bubbles, we computed that the pressure at the tip of the jet is high enough to penetrate any human cell. One image sequence reveals the temporary formation of a liquid drop inside a microbubble.
Conclusions:
Medical microbubble oscillation and translation can be modeled using large, unencapsulated bubble theory. The number of fragments generated by untrasound-induced microbubble break-up has been related to the energy absorbed by the microbubble. Medical bubbles might be used as vehicles that carry a drug to a region of interest, where the release can be controlled with ultrasound. Liquid jets may act as microsyringes, injecting a drug into target tissue. Microbubble phenomena also have potential applications in imaging and noninvasive pressure measurements. Keywords: Microbubble, Ultrasound Affiliations:
Postema M. | - | other affiliation | ten Cate F.J. | - | other affiliation | Lancée C.T. | - | other affiliation | Schmitz G. | - | other affiliation | de Jong N. | - | other affiliation | van Wamel A. | - | other affiliation |
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11. |
Postema M.♦, van Wamel A.♦, Schmitz G.♦, de Jong N.♦, Slingerende belletjes, gerichte medicijnbezorging en microïnjectienaalden,
Klinische fysica, ISSN: 0168-7026, Vol.3+4, pp.6-9, 2004Abstract: Ultrasound contrast agents consist of microscopically small encapsulated bubbles that oscillate upon insonification. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical bubbles have been studied with the aid of high-speed photography. We filmed medical bubbles at higher frame rates than the ultrasonic frequency transmitted. Microbubbles have - among others - been observed to fragment and jet during one single ultrasonic cycle. Gas was released from encapsulated microbubbles. It is concluded that bubbles might act as a vehicle to carry a drug in gas phase to a region of interest, where it has to be released by ultrasound whose amplitudes are still in the diagnostic range. Keywords: Oscillating bubbles, Targeted drug delivery, Micro-injection needles Affiliations:
Postema M. | - | other affiliation | van Wamel A. | - | other affiliation | Schmitz G. | - | other affiliation | de Jong N. | - | other affiliation |
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